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01-10-2020 | Stroke | Original Article

Methylprednisolone Reduces Persistent Post-ischemic Inflammation in a Rat Hypoxia-Ischemia Model of Perinatal Stroke

Authors: Svetlana Altamentova, Prakasham Rumajogee, James Hong, Stephanie R. Beldick, Sei Joon Park, Albert Yee, Michael G. Fehlings

Published in: Translational Stroke Research | Issue 5/2020

Abstract

In perinatal stroke, the initial injury results in a chronic inflammatory response caused by the release of proinflammatory cytokines, gliosis and microglia activation. This chronic and ongoing inflammatory response exacerbates the brain injury, often resulting in encephalopathy and cerebral palsy (CP). Using a neonatal rat model of hypoxia-ischemia (HI) at postnatal day (P)7, we demonstrated that chronic inflammation is persistent and continues into the tertiary phase of perinatal stroke and can be attenuated by the administration of methylprednisolone sodium-succinate (MPSS, 30 mg/kg), a US Food and Drug Administration (FDA) approved anti-inflammatory agent. The inflammatory response was assessed by real-time quantitative PCR and ELISA for markers of inflammation (CCL3, CCL5, IL18 and TNFα). Structural changes were evaluated by histology (LFB/H&E), while cellular changes were assessed by Iba-1, ED1, GFAP, NeuN, Olig2 and CC1 immunostaining. Functional deficits were assessed with the Cylinder test and Ladder Rung Walking test. MPSS was injected 14 days after HI insult to attenuate chronic inflammation. In neonatal conditions such as CP, P21 is a clinically relevant time-point in rodents, corresponding developmentally to a 2-year-old human. Administration of MPSS resulted in reduced structural damage (corpus callosum, cortex, hippocampus, striatum), gliosis and reactive microglia and partial restoration of the oligodendrocyte population. Furthermore, significant behavioural recovery was observed. In conclusion, we demonstrated that administration of MPSS during the tertiary phase of perinatal stroke results in attenuation of the chronic inflammatory response, leading to pathophysiological and functional recovery. This work validates the high clinical impact of MPSS to treat neonatal conditions linked to chronic inflammation.

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de Veber GA, Kirton A, Booth FA, Yager JY, Wirrell EC, Wood E, et al. Epidemiology and outcomes of arterial ischemic stroke in children: the Canadian Pediatric Ischemic Stroke Registry. Pediatr Neurol. 2017;69:58–70. https://doi.org/10.1016/j.pediatrneurol.2017.01.016.CrossRef

Giudice C, Rogers EE, Johnson BC, Glass HC, Shapiro KA. Neuroanatomical correlates of sensory deficits in children with neonatal arterial ischemic stroke. Dev Med Child Neurol. 2018. https://doi.org/10.1111/dmcn.14101.

Nelson KB. Perinatal ischemic stroke. Stroke. 2007;38(2 Suppl):742–5. https://doi.org/10.1161/01.STR.0000247921.97794.5e.CrossRefPubMed

Wagenaar N, Martinez-Biarge M, van der Aa NE, van Haastert IC, Groenendaal F, Benders M, et al. Neurodevelopment after perinatal arterial ischemic stroke. Pediatrics. 2018;142(3). https://doi.org/10.1542/peds.2017-4164.

Kirton A, Deveber G. Life after perinatal stroke. Stroke. 2013;44(11):3265–71. https://doi.org/10.1161/strokeaha.113.000739.CrossRefPubMed

Mineyko A, Kirton A. The black box of perinatal ischemic stroke pathogenesis. J Child Neurol. 2011;26(9):1154–62. https://doi.org/10.1177/0883073811408312.CrossRefPubMedPubMedCentral

Hagberg H, David Edwards A, Groenendaal F. Perinatal brain damage: the term infant. Neurobiol Dis. 2016;92(Pt A):102–12. https://doi.org/10.1016/j.nbd.2015.09.011.CrossRefPubMedPubMedCentral

Van Steenwinckel J, Schang AL, Sigaut S, Chhor V, Degos V, Hagberg H, et al. Brain damage of the preterm infant: new insights into the role of inflammation. Biochem Soc Trans. 2014;42(2):557–63. https://doi.org/10.1042/bst20130284.CrossRefPubMed

Fleiss B, Gressens P. Tertiary mechanisms of brain damage: a new hope for treatment of cerebral palsy? Lancet Neurol. 2012;11(6):556–66. https://doi.org/10.1016/s1474-4422(12)70058-3.CrossRefPubMed

10.

Ek CJ, D’Angelo B, Baburamani AA, Lehner C, Leverin AL, Smith PL, et al. Brain barrier properties and cerebral blood flow in neonatal mice exposed to cerebral hypoxia-ischemia. J Cereb Blood Flow Metab. 2015;35(5):818–27. https://doi.org/10.1038/jcbfm.2014.255.CrossRefPubMedPubMedCentral

11.

Lee WLA, Michael-Titus AT, Shah DK. Hypoxic-ischaemic encephalopathy and the blood-brain barrier in neonates. Dev Neurosci. 2017;39(1–4):49–58. https://doi.org/10.1159/000467392.CrossRefPubMed

12.

Rumajogee P, Bregman T, Miller SP, Yager JY, Fehlings MG. Rodent hypoxia-ischemia models for cerebral palsy research: a systematic review. Front Neurol. 2016;7:57. https://doi.org/10.3389/fneur.2016.00057.CrossRefPubMedPubMedCentral

13.

Hagberg H, Mallard C, Ferriero DM, Vannucci SJ, Levison SW, Vexler ZS, et al. The role of inflammation in perinatal brain injury. Nat Rev Neurol. 2015;11(4):192–208. https://doi.org/10.1038/nrneurol.2015.13.CrossRefPubMedPubMedCentral

14.

Back SA. White matter injury in the preterm infant: pathology and mechanisms. Acta Neuropathol. 2017;134(3):331–49. https://doi.org/10.1007/s00401-017-1718-6.CrossRefPubMedPubMedCentral

15.

Fern RF, Matute C, Stys PK. White matter injury: ischemic and nonischemic. Glia. 2014;62(11):1780–9. https://doi.org/10.1002/glia.22722.CrossRefPubMed

16.

Liu F, McCullough LD. Inflammatory responses in hypoxic ischemic encephalopathy. Acta Pharmacol Sin. 2013;34(9):1121–30. https://doi.org/10.1038/aps.2013.89.CrossRefPubMedPubMedCentral

17.

Favrais G, van de Looij Y, Fleiss B, Ramanantsoa N, Bonnin P, Stoltenburg-Didinger G, et al. Systemic inflammation disrupts the developmental program of white matter. Ann Neurol. 2011;70(4):550–65. https://doi.org/10.1002/ana.22489.CrossRefPubMed

18.

Ramaswamy V, Miller SP, Barkovich AJ, Partridge JC, Ferriero DM. Perinatal stroke in term infants with neonatal encephalopathy. Neurology. 2004;62(11):2088–91. https://doi.org/10.1212/01.WNL.0000129909.77753.C4.CrossRefPubMed

19.

Chalak LF, Sanchez PJ, Adams-Huet B, Laptook AR, Heyne RJ, Rosenfeld CR. Biomarkers for severity of neonatal hypoxic-ischemic encephalopathy and outcomes in newborns receiving hypothermia therapy. J Pediatr. 2014;164(3):468–74.e1. https://doi.org/10.1016/j.jpeds.2013.10.067.CrossRefPubMed

20.

Bhalala US, Koehler RC, Kannan S. Neuroinflammation and neuroimmune dysregulation after acute hypoxic-ischemic injury of developing brain. Front Pediatr. 2014;2:144. https://doi.org/10.3389/fped.2014.00144.CrossRefPubMed

21.

Bona E, Andersson A-L, Blomgren K, Gilland E, Puka-Sundvall M, Gustafson K, et al. Chemokine and inflammatory cell response to hypoxia-ischemia in immature rats. Pediatr Res. 1999;45:500. https://doi.org/10.1203/00006450-199904010-00008.CrossRefPubMed

22.

Hedtjarn M, Mallard C, Arvidsson P, Hagberg H. White matter injury in the immature brain: role of interleukin-18. Neurosci Lett. 2005;373(1):16–20. https://doi.org/10.1016/j.neulet.2004.09.062.CrossRefPubMed

23.

Hedtjarn M, Leverin AL, Eriksson K, Blomgren K, Mallard C, Hagberg H. Interleukin-18 involvement in hypoxic-ischemic brain injury. J Neurosci. 2002;22(14):5910–9.CrossRef

24.

Daneyemez M, Kurt E, Cosar A, Yuce E, Ide T. Methylprednisolone and vitamin E therapy in perinatal hypoxic-ischemic brain damage in rats. Neuroscience. 1999;92(2):693–7.CrossRef

25.

Gonzalez-Rodriguez PJ, Li Y, Martinez F, Zhang L. Dexamethasone protects neonatal hypoxic-ischemic brain injury via L-PGDS-dependent PGD2-DP1-pERK signaling pathway. PLoS One. 2014;9(12):e114470. https://doi.org/10.1371/journal.pone.0114470.CrossRefPubMedPubMedCentral

26.

Harding B, Conception K, Li Y, Zhang L. Glucocorticoids protect neonatal rat brain in model of hypoxic-ischemic encephalopathy (HIE). Int J Mol Sci. 2016;18(1). https://doi.org/10.3390/ijms18010017.

27.

Concepcion KR, Zhang L. Corticosteroids and perinatal hypoxic-ischemic brain injury. Drug Discov Today. 2018. https://doi.org/10.1016/j.drudis.2018.05.019.

28.

Cheng S, Gao W, Xu X, Fan H, Wu Y, Li F, et al. Methylprednisolone sodium succinate reduces BBB disruption and inflammation in a model mouse of intracranial haemorrhage. Brain Res Bull. 2016;127:226–33. https://doi.org/10.1016/j.brainresbull.2016.10.007.CrossRefPubMed

29.

Kim JS, Chopp M, Gautam SC. High dose methylprednisolone therapy reduces expression of JE/MCP-1 mRNA and macrophage accumulation in the ischemic rat brain. J Neurol Sci. 1995;128(1):28–35.CrossRef

30.

Hall ED. Methylprednisolone for the treatment of patients with acute spinal cord injuries: a propensity score-matched cohort study from a Canadian Multi-Center Spinal Cord Injury Registry. J Neurotrauma. 2016;33(10):972–4. https://doi.org/10.1089/neu.2016.4473.CrossRefPubMed

31.

Cooper SD, Felkins K, Baker TE, Hale TW. Transfer of methylprednisolone into breast milk in a mother with multiple sclerosis. J Hum Lact. 2015;31(2):237–9. https://doi.org/10.1177/0890334415570970.CrossRefPubMed

32.

Fehlings MG, Wilson JR, Harrop JS, Kwon BK, Tetreault LA, Arnold PM, et al. Efficacy and safety of methylprednisolone sodium succinate in acute spinal cord injury: a systematic review. Glob Spine J. 2017;7(3 Suppl):116S–37S. https://doi.org/10.1177/2192568217706366.CrossRef

33.

Fernandes Moca Trevisani V, Castro AA, Ferreira Neves Neto J, Atallah AN. Cyclophosphamide versus methylprednisolone for treating neuropsychiatric involvement in systemic lupus erythematosus. Cochrane Database Syst Rev. 2013;(2):CD002265. https://doi.org/10.1002/14651858.CD002265.pub3.

34.

Hall ED. The neuroprotective pharmacology of methylprednisolone. J Neurosurg. 1992;76(1):13–22. https://doi.org/10.3171/jns.1992.76.1.0013.CrossRefPubMed

35.

Oudega M, Vargas CG, Weber AB, Kleitman N, Bunge MB. Long-term effects of methylprednisolone following transection of adult rat spinal cord. Eur J Neurosci. 1999;11(7):2453–64.CrossRef

36.

Bansal LR. Therapeutic effect of steroids in osmotic demyelination of infancy. Child Neurol Open. 2018;5:2329048x18770576. https://doi.org/10.1177/2329048x18770576.CrossRefPubMedPubMedCentral

37.

Graham HK, Rosenbaum P, Paneth N, Dan B, Lin JP, Damiano DL, et al. Cerebral palsy. Nat Rev Dis Prim. 2016;2:15082. https://doi.org/10.1038/nrdp.2015.82.CrossRefPubMed

38.

Hubermann L, Boychuck Z, Shevell M, Majnemer A. Age at referral of children for initial diagnosis of cerebral palsy and rehabilitation: current practices. J Child Neurol. 2016;31(3):364–9. https://doi.org/10.1177/0883073815596610.CrossRefPubMed

39.

Semple BD, Blomgren K, Gimlin K, Ferriero DM, Noble-Haeusslein LJ. Brain development in rodents and humans: Identifying benchmarks of maturation and vulnerability to injury across species. Prog Neurobiol. 2013:106, 1–7, 16. https://doi.org/10.1016/j.pneurobio.2013.04.001.

40.

Rice JE 3rd, Vannucci RC, Brierley JB. The influence of immaturity on hypoxic-ischemic brain damage in the rat. Ann Neurol. 1981;9(2):131–41. https://doi.org/10.1002/ana.410090206.CrossRefPubMed

41.

Vannucci RC, Vannucci SJ. Perinatal hypoxic-ischemic brain damage: evolution of an animal model. Dev Neurosci. 2005;27(2–4):81–6. https://doi.org/10.1159/000085978.CrossRefPubMed

42.

Rumajogee P, Altamentova S, Li L, Li J, Wang J, Kuurstra A, et al. Exogenous neural precursor cell transplantation results in structural and functional recovery in a hypoxic-ischemic hemiplegic mouse model. eNeuro. 2018;5(5). https://doi.org/10.1523/eneuro.0369-18.2018.

43.

Kalayci O, Cataltepe S, Cataltepe O. The effect of bolus methylprednisolone in prevention of brain edema in hypoxic ischemic brain injury: an experimental study in 7-day-old rat pups. Brain Res. 1992;569(1):112–6.CrossRef

44.

Yu Y, Matsuyama Y, Nakashima S, Yanase M, Kiuchi K, Ishiguro N. Effects of MPSS and a potent iNOS inhibitor on traumatic spinal cord injury. Neuroreport. 2004;15(13):2103–7.CrossRef

45.

Braughler JM, Hall ED. Effects of multi-dose methylprednisolone sodium succinate administration on injured cat spinal cord neurofilament degradation and energy metabolism. J Neurosurg. 1984;61(2):290–5. https://doi.org/10.3171/jns.1984.61.2.0290.CrossRefPubMed

46.

Jing Y, Hou Y, Song Y, Yin J. Methylprednisolone improves the survival of new neurons following transient cerebral ischemia in rats. Acta Neurobiol Exp. 2012;72(3):240–52.

47.

Braughler JM, Hall ED. Correlation of methylprednisolone levels in cat spinal cord with its effects on (Na+ + K+)-ATPase, lipid peroxidation, and alpha motor neuron function. J Neurosurg. 1982;56(6):838–44. https://doi.org/10.3171/jns.1982.56.6.0838.CrossRefPubMed

48.

Hall ED, Braughler JM, McCall JM. Antioxidant effects in brain and spinal cord injury. J Neurotrauma. 1992;9(Suppl 1):S165–72.PubMed

49.

Hall ED, Wolf DL, Braughler JM. Effects of a single large dose of methylprednisolone sodium succinate on experimental posttraumatic spinal cord ischemia. Dose-response and time-action analysis. J Neurosurg. 1984;61(1):124–30. https://doi.org/10.3171/jns.1984.61.1.0124.CrossRefPubMed

50.

Vidal PM, Ulndreaj A, Badner A, Hong J, Fehlings MG. Methylprednisolone treatment enhances early recovery following surgical decompression for degenerative cervical myelopathy without compromise to the systemic immune system. J Neuroinflammation. 2018;15(1):222. https://doi.org/10.1186/s12974-018-1257-7.CrossRefPubMedPubMedCentral

51.

Forgione N, Chamankhah M, Fehlings MG. A mouse model of bilateral cervical contusion-compression spinal cord injury. J Neurotrauma. 2017;34(6):1227–39. https://doi.org/10.1089/neu.2016.4708.CrossRefPubMed

52.

Cai J, Kang Z, Liu WW, Luo X, Qiang S, Zhang JH, et al. Hydrogen therapy reduces apoptosis in neonatal hypoxia-ischemia rat model. Neurosci Lett. 2008;441(2):167–72. https://doi.org/10.1016/j.neulet.2008.05.077.CrossRefPubMed

53.

Ruff CA, Ye H, Legasto JM, Stribbell NA, Wang J, Zhang L, et al. Effects of adult neural precursor-derived myelination on axonal function in the perinatal congenitally dysmyelinated brain: optimizing time of intervention, developing accurate prediction models, and enhancing performance. J Neurosci. 2013;33(29):11899–915. https://doi.org/10.1523/JNEUROSCI.1131-13.2013.CrossRefPubMedPubMedCentral

54.

Karimi-Abdolrezaee S, Eftekharpour E, Wang J, Schut D, Fehlings MG. Synergistic effects of transplanted adult neural stem/progenitor cells, chondroitinase, and growth factors promote functional repair and plasticity of the chronically injured spinal cord. J Neurosci. 2010;30(5):1657–76. https://doi.org/10.1523/JNEUROSCI.3111-09.2010.CrossRefPubMedPubMedCentral

55.

Beldick SR, Hong J, Altamentova S, Khazaei M, Hundal A, Zavvarian MM, et al. Severe-combined immunodeficient rats can be used to generate a model of perinatal hypoxic-ischemic brain injury to facilitate studies of engrafted human neural stem cells. PLoS One. 2018;13(11):e0208105. https://doi.org/10.1371/journal.pone.0208105.CrossRefPubMedPubMedCentral

56.

Goto N. Discriminative staining methods for the nervous system: luxol fast blue--periodic acid-Schiff--hematoxylin triple stain and subsidiary staining methods. Stain Technol. 1987;62(5):305–15.CrossRef

57.

Metz GA, Whishaw IQ. Cortical and subcortical lesions impair skilled walking in the ladder rung walking test: a new task to evaluate fore- and hindlimb stepping, placing, and co-ordination. J Neurosci Methods. 2002;115(2):169–79.CrossRef

58.

Fleiss B, Tann CJ, Degos V, Sigaut S, Van Steenwinckel J, Schang AL, et al. Inflammation-induced sensitization of the brain in term infants. Dev Med Child Neurol. 2015;57(Suppl 3):17–28. https://doi.org/10.1111/dmcn.12723.CrossRefPubMed

59.

Moretti R, Pansiot J, Bettati D, Strazielle N, Ghersi-Egea JF, Damante G, et al. Blood-brain barrier dysfunction in disorders of the developing brain. Front Neurosci. 2015;9:40. https://doi.org/10.3389/fnins.2015.00040.CrossRefPubMedPubMedCentral

60.

Shrivastava K, Llovera G, Recasens M, Chertoff M, Gimenez-Llort L, Gonzalez B, et al. Temporal expression of cytokines and signal transducer and activator of transcription factor 3 activation after neonatal hypoxia/ischemia in mice. Dev Neurosci. 2013;35(2–3):212–25. https://doi.org/10.1159/000348432.CrossRefPubMed

61.

Ikeda T, Mishima K, Aoo N, Liu AX, Egashira N, Iwasaki K, et al. Dexamethasone prevents long-lasting learning impairment following a combination of lipopolysaccharide and hypoxia-ischemia in neonatal rats. Am J Obstet Gynecol. 2005;192(3):719–26. https://doi.org/10.1016/j.ajog.2004.12.048.CrossRefPubMed

62.

Benveniste EN. Inflammatory cytokines within the central nervous system: sources, function, and mechanism of action. Am J Phys. 1992;263(1 Pt 1):C1–16. https://doi.org/10.1152/ajpcell.1992.263.1.C1.CrossRef

63.

Benveniste EN. Cytokines: influence on glial cell gene expression and function. Chem Immunol. 1992;52:106–53.PubMed

64.

Ramesh G, MacLean AG, Philipp MT. Cytokines and chemokines at the crossroads of neuroinflammation, neurodegeneration, and neuropathic pain. Mediat Inflamm. 2013;2013:480739. https://doi.org/10.1155/2013/480739.CrossRef

65.

Okada S, Nakamura M, Mikami Y, Shimazaki T, Mihara M, Ohsugi Y, et al. Blockade of interleukin-6 receptor suppresses reactive astrogliosis and ameliorates functional recovery in experimental spinal cord injury. J Neurosci Res. 2004;76(2):265–76. https://doi.org/10.1002/jnr.20044.CrossRefPubMed

66.

Donnelly DJ, Popovich PG. Inflammation and its role in neuroprotection, axonal regeneration and functional recovery after spinal cord injury. Exp Neurol. 2008;209(2):378–88. https://doi.org/10.1016/j.expneurol.2007.06.009.CrossRefPubMed

67.

Taib T, Leconte C, Van Steenwinckel J, Cho AH, Palmier B, Torsello E, et al. Neuroinflammation, myelin and behavior: temporal patterns following mild traumatic brain injury in mice. PLoS One. 2017;12(9):e0184811. https://doi.org/10.1371/journal.pone.0184811.CrossRefPubMedPubMedCentral

68.

Ashwell JD, Lu FW, Vacchio MS. Glucocorticoids in T cell development and function*. Annu Rev Immunol. 2000;18:309–45. https://doi.org/10.1146/annurev.immunol.18.1.309.CrossRefPubMed

69.

Mathian A, Jouenne R, Chader D, Cohen-Aubart F, Haroche J, Fadlallah J, et al. Regulatory T cell responses to high-dose methylprednisolone in active systemic lupus Erythematosus. PLoS One. 2015;10(12):e0143689. https://doi.org/10.1371/journal.pone.0143689.CrossRefPubMedPubMedCentral

70.

Sbiera S, Dexneit T, Reichardt SD, Michel KD, van den Brandt J, Schmull S, et al. Influence of short-term glucocorticoid therapy on regulatory T cells in vivo. PLoS One. 2011;6(9):e24345. https://doi.org/10.1371/journal.pone.0024345.CrossRefPubMedPubMedCentral

71.

Jobe AH. Glucocorticoids in perinatal medicine: misguided rockets? J Pediatr. 2000;137(1):1–3. https://doi.org/10.1067/mpd.2000.107801.CrossRefPubMed

72.

Baud O, Sola A. Corticosteroids in perinatal medicine: how to improve outcomes without affecting the developing brain? Semin Fetal Neonatal Med. 2007;12(4):273–9. https://doi.org/10.1016/j.siny.2007.01.025.CrossRefPubMed

73.

Bennet L, Davidson JO, Koome M, Gunn AJ. Glucocorticoids and preterm hypoxic-ischemic brain injury: the good and the bad. J Pregnancy. 2012;2012:751694. https://doi.org/10.1155/2012/751694.CrossRefPubMedPubMedCentral

74.

Damsted SK, Born AP, Paulson OB, Uldall P. Exogenous glucocorticoids and adverse cerebral effects in children. Eur J Paediatr Neurol. 2011;15(6):465–77. https://doi.org/10.1016/j.ejpn.2011.05.002.CrossRefPubMed

75.

Tuor UI, Chumas PD, Del Bigio MR. Prevention of hypoxic-ischemic damage with dexamethasone is dependent on age and not influenced by fasting. Exp Neurol. 1995;132(1):116–22. https://doi.org/10.1016/0014-4886(95)90065-9.CrossRefPubMed

76.

Aljebab F, Choonara I, Conroy S. Systematic review of the toxicity of short-course oral corticosteroids in children. Arch Dis Child. 2016;101(4):365–70. https://doi.org/10.1136/archdischild-2015-309522.CrossRefPubMedPubMedCentral

77.

Baud O. Postnatal steroid treatment and brain development. Arch Dis Child Fetal Neonatal Ed. 2004;89(2):F96–100.CrossRef

78.

O’Shea TM, Doyle LW. Perinatal glucocorticoid therapy and neurodevelopmental outcome: an epidemiologic perspective. Semin Neonatol. 2001;6(4):293–307. https://doi.org/10.1053/siny.2001.0065.CrossRefPubMed

79.

Malaeb SN, Stonestreet BS. Steroids and injury to the developing brain: net harm or net benefit? Clin Perinatol. 2014;41(1):191–208. https://doi.org/10.1016/j.clp.2013.09.006.CrossRefPubMedPubMedCentral

Title: Methylprednisolone Reduces Persistent Post-ischemic Inflammation in a Rat Hypoxia-Ischemia Model of Perinatal Stroke
Authors: Svetlana Altamentova
Prakasham Rumajogee
James Hong
Stephanie R. Beldick
Sei Joon Park
Albert Yee
Michael G. Fehlings
Publication date: 01-10-2020
Publisher: Springer US
Keyword: Stroke
Published in: Translational Stroke Research / Issue 5/2020
Print ISSN: 1868-4483
Electronic ISSN: 1868-601X
DOI: https://doi.org/10.1007/s12975-020-00792-2

At a glance: The STEP trials

Springer Medicine

Methylprednisolone Reduces Persistent Post-ischemic Inflammation in a Rat Hypoxia-Ischemia Model of Perinatal Stroke

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

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